Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adjuvant Colon Cancer
Table 4 shows the adverse reactions occurring in ≥ 5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m² twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabinetreated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV.
Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥ 1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.
Table 4 : Percent Incidence of Adverse Reactions Reported in ≥ 5% of Patients Treated With XELODA or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)
Body System/Adverse Event | Adjuvant Treatment for Colon Cancer (N=1969) |
|||
XELODA (N=995) |
5-FU/LV (N=974) |
|||
All Grades | Grade 3/4 | All Grades | Grade 3/4 | |
Gastrointestinal Disorders | ||||
Diarrhea | 47 | 12 | 65 | 14 |
Nausea | 34 | 2 | 47 | 2 |
Stomatitis | 22 | 2 | 60 | 14 |
Vomiting | 15 | 2 | 21 | 2 |
Abdominal Pain | 14 | 3 | 16 | 2 |
Constipation | 9 | - | 11 | < 1 |
Upper Abdominal Pain | 7 | < 1 | 7 | < 1 |
Dyspepsia | 6 | < 1 | 5 | - |
Skin and Subcutaneous Tissue Disorders | ||||
Hand-and-Foot | 60 | 17 | 9 | < 1 |
Syndrome | ||||
Alopecia | 6 | - | 22 | < 1 |
Rash | 7 | - | 8 | - |
Erythema | 6 | 1 | 5 | < 1 |
General Disorders and Administration Site Conditions | ||||
Fatigue | 16 | < 1 | 16 | 1 |
Pyrexia | 7 | < 1 | 9 | < 1 |
Asthenia | 10 | < 1 | 10 | 1 |
Lethargy | 10 | < 1 | 9 | < 1 |
Nervous System Disorders | ||||
Dizziness | 6 | < 1 | 6 | - |
Headache | 5 | < 1 | 6 | < 1 |
Dysgeusia | 6 | - | 9 | - |
Metabolism and Nutrition Disorders | ||||
Anorexia | 9 | < 1 | 11 | < 1 |
Eye Disorders | ||||
Conjunctivitis | 5 | < 1 | 6 | < 1 |
Blood and Lymphatic System Disorders | ||||
Neutropenia | 2 | < 1 | 8 | 5 |
Respiratory Thoracic and Mediastinal Disorders | ||||
Epistaxis | 2 | - | 5 | - |
Table 5 : Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Patients Receiving XELODA Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)
Adverse Event | XELODA (n=995) Grade 3/4 % |
IV 5-FU/LV (n=974) Grade 3/4 % |
Increased ALAT (SGPT) | 1.6 | 0.6 |
Increased calcium | 1.1 | 0.7 |
Decreased calcium | 2.3 | 2.2 |
Decreased hemoglobin | 1.0 | 1.2 |
Decreased lymphocytes | 13.0 | 13.0 |
Decreased neutrophils* | 2.2 | 26.2 |
Decreased neutrophils/granulocytes | 2.4 | 26.4 |
Decreased platelets | 1.0 | 0.7 |
Increased bilirubin** | 20 | 6.3 |
*The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA arm and 4.9% in the IV 5FU/LV arm. **It should be noted that grading was according to NCIC CTC Version 1 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of > 3.0 to 10.0 × ULN, and grade 4 values > 10.0 × ULN. |
Metastatic Colorectal Cancer
Monotherapy
Table 6 shows the adverse reactions occurring in ≥ 5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m² twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV.
Table 6 : Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥ 5% of Patients
Adverse Event | XELODA (n=596) | 5-FU/LV (n=593) | ||||
Total % | Grade 3 % | Grade 4 % | Total % | Grade 3 % | Grade 4 % | |
Number of Patients With > One Adverse Event | 96 | 52 | 9 | 94 | 45 | 9 |
Body System/Adverse Event | ||||||
GI | ||||||
Diarrhea | 55 | 13 | 2 | 61 | 10 | 2 |
Nausea | 43 | 4 | - | 51 | 3 | < 1 |
Vomiting | 27 | 4 | < 1 | 30 | 4 | < 1 |
Stomatitis | 25 | 2 | < 1 | 62 | 14 | 1 |
Abdominal Pain | 35 | 9 | < 1 | 31 | 5 | - |
Gastrointestinal Motility Disorder | 10 | < 1 | - | 7 | < 1 | - |
Constipation | 14 | 1 | < 1 | 17 | 1 | - |
Oral Discomfort | 10 | - | - | 10 | - | - |
Upper GI Inflammatory Disorders | 8 | < 1 | - | 10 | 1 | - |
Gastrointestinal Hemorrhage | 6 | 1 | < 1 | 3 | 1 | - |
Ileus | 6 | 4 | 1 | 5 | 2 | 1 |
Skin and Subcutaneous | ||||||
Hand-and-Foot Syndrome | 54 | 17 | NA | 6 | 1 | NA |
Dermatitis | 27 | 1 | - | 26 | 1 | - |
Skin Discoloration | 7 | < 1 | - | 5 | - | - |
Alopecia | 6 | - | - | 21 | < 1 | - |
General | ||||||
Fatigue/Weakness | 42 | 4 | - | 46 | 4 | - |
Pyrexia | 18 | 1 | - | 21 | 2 | - |
Edema | 15 | 1 | - | 9 | 1 | - |
Pain | 12 | 1 | - | 10 | 1 | - |
Chest Pain | 6 | 1 | - | 6 | 1 | < 1 |
Neurological | ||||||
Peripheral Sensory Neuropathy | 10 | - | - | 4 | - | - |
Headache | 10 | 1 | - | 7 | - | - |
Dizziness* | 8 | < 1 | - | 8 | < 1 | - |
Insomnia | 7 | - | - | 7 | - | - |
Taste Disturbance | 6 | 1 | - | 11 | < 1 | 1 |
Metabolism | ||||||
Appetite Decreased | 26 | 3 | < 1 | 31 | 2 | < 1 |
Dehydration | 7 | 2 | < 1 | 8 | 3 | 1 |
Eye | ||||||
Eye Irritation | 13 | - | - | 10 | < 1 | - |
Vision Abnormal | 5 | - | - | 2 | - | - |
Respiratory | ||||||
Dyspnea | 14 | 1 | - | 10 | < 1 | 1 |
Cough | 7 | < 1 | 1 | 8 | - | - |
Pharyngeal Disorder | 5 | - | - | 5 | - | - |
Epistaxis | 3 | < 1 | - | 6 | - | - |
Sore Throat | 2 | - | - | 6 | - | - |
Musculoskeletal | ||||||
Back Pain | 10 | 2 | - | 9 | < 1 | - |
Arthralgia | 8 | 1 | - | 6 | 1 | - |
Vascular | ||||||
Venous Thrombosis | 8 | 3 | < 1 | 6 | 2 | - |
Psychiatric | ||||||
Mood Alteration | 5 | - | - | 6 | < 1 | - |
Depression | 5 | - | - | 4 | < 1 | - |
Infections | ||||||
Viral | 5 | < 1 | - | 5 | < 1 | - |
Blood and Lymphatic | ||||||
Anemia | 80 | 2 | < 1 | 79 | 1 | < 1 |
Neutropenia | 13 | 1 | 2 | 46 | 8 | 13 |
Hepatobiliary | ||||||
Hyperbilirubinemia | 48 | 18 | 5 | 17 | 3 | 3 |
– Not observed * Excluding vertigo NA = Not Applicable |
Breast Cancer
In Combination with Docetaxel
The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m² twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m² on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m² on the first day of each 3week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.
Table 7 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥ 5% of Patients Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study
Adverse Event | XELODA 1250 mg/m²/bid With Docetaxel 75 mg/m²/3 weeks (n=251) | Docetaxel 100 mg/m²/3 weeks (n=255) | ||||
Total % | Grade 3 % | Grade 4 % | Total % | Grade 3 % | Grade 4 % | |
Number of Patients With at Least One Adverse Event | 99 | 76.5 | 29.1 | 97 | 57.6 | 31.8 |
Body System/Adverse Event | ||||||
GI | ||||||
Diarrhea | 67 | 14 | < 1 | 48 | 5 | < 1 |
Stomatitis | 67 | 17 | < 1 | 43 | 5 | - |
Nausea | 45 | 7 | - | 36 | 2 | - |
Vomiting | 35 | 4 | 1 | 24 | 2 | - |
Constipation | 20 | 2 | - | 18 | - | - |
Abdominal Pain | 30 | < 3 | < 1 | 24 | 2 | - |
Dyspepsia | 14 | - | - | 8 | 1 | - |
Dry Mouth | 6 | < 1 | - | 5 | - | - |
Skin and Subcutaneous | ||||||
Hand-and-Foot Syndrome | 63 | 24 | NA | 8 | 1 | NA |
Alopecia | 41 | 6 | - | 42 | 7 | - |
Nail Disorder | 14 | 2 | - | 15 | - | - |
Dermatitis | 8 | - | - | 11 | 1 | - |
Rash Erythematous | 9 | < 1 | - | 5 | - | - |
Nail Discoloration | 6 | - | - | 4 | < 1 | - |
Onycholysis | 5 | 1 | - | 5 | 1 | - |
Pruritus | 4 | - | - | 5 | - | - |
General | ||||||
Pyrexia | 28 | 2 | - | 34 | 2 | - |
Asthenia | 26 | 4 | < 1 | 25 | 6 | - |
Fatigue | 22 | 4 | - | 27 | 6 | - |
Weakness | 16 | 2 | - | 11 | 2 | - |
Pain in Limb | 13 | < 1 | - | 13 | 2 | - |
Lethargy | 7 | - | - | 6 | 2 | - |
Pain | 7 | < 1 | - | 5 | 1 | - |
Chest Pain (non-cardiac) | 4 | < 1 | - | 6 | 2 | - |
Influenza-like Illness | 5 | - | - | 5 | - | - |
Neurological | ||||||
Taste Disturbance | 16 | < 1 | - | 14 | < 1 | - |
Headache | 15 | 3 | - | 15 | 2 | - |
Paresthesia | 12 | < 1 | - | 16 | 1 | - |
Dizziness | 12 | - | - | 8 | < 1 | - |
Insomnia | 8 | - | - | 10 | < 1 | - |
Peripheral Neuropathy | 6 | - | - | 10 | 1 | - |
Hypoaesthesia | 4 | < 1 | - | 8 | < 1 | - |
Metabolism | ||||||
Anorexia | 13 | 1 | - | 11 | < 1 | - |
Appetite Decreased | 10 | - | - | 5 | - | - |
Weight Decreased | 7 | - | - | 5 | - | - |
Dehydration | 10 | 2 | - | 7 | < 1 | < 1 |
Eye | ||||||
Lacrimation Increased | 12 | - | - | 7 | < 1 | - |
Conjunctivitis | 5 | - | - | 4 | - | - |
Eye Irritation | 5 | - | - | 1 | - | - |
Musculoskeletal | ||||||
Arthralgia | 15 | 2 | - | 24 | 3 | - |
Myalgia | 15 | 2 | - | 25 | 2 | - |
Back Pain | 12 | < 1 | - | 11 | 3 | - |
Bone Pain | 8 | < 1 | - | 10 | 2 | - |
Cardiac | ||||||
Edema | 33 | < 2 | - | 34 | < 3 | 1 |
Blood | ||||||
Neutropenic Fever | 16 | 3 | 13 | 21 | 5 | 16 |
Respiratory | ||||||
Dyspnea | 14 | 2 | < 1 | 16 | 2 | - |
Cough | 13 | 1 | - | 22 | < 1 | - |
Sore Throat | 12 | 2 | - | 11 | < 1 | - |
Epistaxis | 7 | < 1 | - | 6 | - | - |
Rhinorrhea | 5 | - | - | 3 | - | - |
Pleural Effusion | 2 | 1 | - | 7 | 4 | - |
Infection | ||||||
Oral Candidiasis | 7 | < 1 | - | 8 | < 1 | - |
Urinary Tract Infection | 6 | < 1 | - | 4 | - | - |
Upper Respiratory Tract | 4 | - | - | 5 | 1 | - |
Vascular | ||||||
Flushing | 5 | - | - | 5 | - | - |
Lymphoedema | 3 | < 1 | - | 5 | 1 | - |
Psychiatric | ||||||
Depression | 5 | - | - | 5 | 1 | - |
Table 8 : Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study
Adverse Event | XELODA 1250 mg/m²/bid With Docetaxel 75 mg/m²/3 weeks (n=251) | Docetaxel 100 mg/m²/3 weeks (n=255) | ||||
Body System/Adverse Event | Total % | Grade 3 % | Grade 4 % | Total % | Grade 3 % | Grade 4 % |
Hematologic | ||||||
Leukopenia | 91 | 37 | 24 | 88 | 42 | 33 |
Neutropenia/ Granulocytopenia | 86 | 20 | 49 | 87 | 10 | 66 |
Thrombocytopenia | 41 | 2 | 1 | 23 | 1 | 2 |
Anemia | 80 | 7 | 3 | 83 | 5 | < 1 |
Lymphocytopenia | 99 | 48 | 41 | 98 | 44 | 40 |
Hepatobiliary | ||||||
Hyperbilirubinemia | 20 | 7 | 2 | 6 | 2 | 2 |
Monotherapy
The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m² administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.
Table 9 : Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in ≥ 5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer
Adverse Event | Phase 2 Trial in Stage IV Breast Cancer (n=162) |
||
Body System/Adverse Event | Total % | Grade 3 % | Grade 4 % |
GI | |||
Diarrhea | 57 | 12 | 3 |
Nausea | 53 | 4 | - |
Vomiting | 37 | 4 | - |
Stomatitis | 24 | 7 | - |
Abdominal Pain | 20 | 4 | - |
Constipation | 15 | 1 | - |
Dyspepsia | 8 | - | - |
Skin and Subcutaneous | |||
Hand-and-Foot Syndrome | 57 | 11 | NA |
Dermatitis | 37 | 1 | - |
Nail Disorder | 7 | - | - |
General | |||
Fatigue | 41 | 8 | - |
Pyrexia | 12 | 1 | - |
Pain in Limb | 6 | 1 | - |
Neurological | |||
Paresthesia | 21 | 1 | - |
Headache | 9 | 1 | - |
Dizziness | 8 | - | - |
Insomnia | 8 | - | - |
Metabolism | |||
Anorexia | 23 | 3 | - |
Dehydration | 7 | 4 | 1 |
Eye | |||
Eye Irritation | 15 | - | - |
Musculoskeletal | |||
Myalgia | 9 | - | - |
Cardiac Edema | 9 | 1 | |
Blood | |||
Neutropenia | 26 | 2 | 2 |
Thrombocytopenia | 24 | 3 | 1 |
Anemia | 72 | 3 | 1 |
Lymphopenia | 94 | 44 | 15 |
Hepatobiliary | |||
Hyperbilirubinemia | 22 | 9 | 2 |
– Not observed NA = Not Applicable |
Clinically Relevant Adverse Events In < 5% Of Patients
Clinically relevant adverse events reported in < 5% of patients treated with XELODA either as monotherapy or in combination with docetaxol that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses.
Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%)
Skin & Subcutan.: nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%)
General: chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation
Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance
Metabolism: increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia
Eye: conjunctivitis
Respiratory: cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea
Cardiac: tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion
Infections: laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%)
Musculoskeletal: myalgia, bone pain (0.1%), arthritis (0.1%), muscle weakness
Blood & Lymphatic: leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%)
Vascular: hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%)
Psychiatric: depression, confusion (0.1%)
Renal: renal impairment (0.6%)
Ear: vertigo
Hepatobiliary: hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function tests
Immune System: drug hypersensitivity (0.1%)
Postmarketing: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see WARNINGS AND PRECAUTIONS], cutaneous lupus erythematosus, corneal disorders including keratitis, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see WARNINGS AND PRECAUTIONS]
XELODA In Combination With Docetaxel (Metastatic Breast Cancer)
Gastrointestinal: ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%)
Neurological: ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%)
Cardiac: supraventricular tachycardia (0.4%)
Infection: neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%)
Blood & Lymphatic: agranulocytosis (0.4%), prothrombin decreased (0.4%)
Vascular: hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%)
Renal: renal failure (0.4%)
Hepatobiliary: jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%)
Immune System: hypersensitivity (1.2%)